Neurobiological Correlates of Fear in Veterans with Military Sexual Trauma

描述(由申请人提供)： 暴露在导致极度恐惧、恐惧或无助的创伤性事件中会导致焦虑症，如创伤后应激障碍(PTSD)，这通常会与抑郁症并存。经历过军需性创伤(MST)的女性退伍军人特别容易出现与创伤相关的各种心理和身体健康问题，包括创伤后应激障碍、抑郁、焦虑、慢性疼痛、睡眠障碍、药物滥用、广泛的身体症状和消极的健康行为。个别患者出现不同症状群的程度可能有所不同，因此“一刀切”的治疗往往是不够的。这种个体变异可能与增加疾病易感性或阻碍治疗的生物风险因素有关。虽然神经生物学因素(如激素、基因组学)相互作用会增加个体患创伤后应激障碍的风险，但尚不清楚这些因素如何影响潜在的神经生物学，从而导致观察到的失调。创伤后应激障碍的特点是边缘系统的皮质控制受损，特别是杏仁核和海马体。恐惧条件作用方法提供了强大的基于大脑的创伤后应激障碍风险表型，无论创伤类型如何，这在平民和战斗后创伤后应激障碍人群中都可以观察到。这项拟议的研究将利用这一可观察到的标记物和MST患者的个体差异性来研究创伤后应激障碍的神经生物学基础以及这种表型在预测治疗反应方面的作用。使用最先进的分子遗传学方法，结合对恐惧回路的机械性理解，将提供对Traum风险和弹性的个体差异的巨大洞察。恐惧反应将使用经过验证的恐惧强化惊吓范式进行观察，该范式允许研究人员评估条件性恐惧反应的获得、消退和回归。这项研究将通过测量女性退伍军人群体中的雌激素变化来研究荷尔蒙对增强恐惧反应的贡献。ADCYAP1R1基因编码垂体腺苷环化酶激活多肽(PACAP)的1型受体(PAC1)，是创伤后女性创伤后应激障碍的主要候选基因之一。这种遗传多态是使用假设中性基因组收敛方法鉴定的，但此后在几个不同的创伤后应激障碍研究人群中重复出现。拟议的项目将包括检查PAC1基因、甲基化状态、mRNA表达和雌激素变异对创伤后应激障碍症状表达的影响，以及对研究不足的女性退伍军人群体进行恐惧和焦虑的实验室测量。最后，我们将评估将纳入 与亚特兰大VAMC创伤恢复计划内的创伤后应激障碍治疗结果相关的拟议工作。

DESCRIPTION (provided by applicant): Exposure to a traumatic event that causes extreme fear, horror or helplessness can lead to anxiety disorders, such as posttraumatic stress disorder (PTSD), which can often be co-morbid with depression. Female Veterans who experienced Military Sexual Trauma (MST) are particularly at risk for a wide range of trauma- related mental and physical health problems including PTSD, depression, anxiety, chronic pain, sleep disturbances, substance abuse, wide-ranging physical symptoms, and negative health behaviors. Individual patients can vary in the degree to which they present with the different symptom clusters, such that a "one size fits all" treatment is often inadequate. This individual variation may be associated with biological risk factors that increase vulnerability to the disorder or impede treatment. While neurobiological factors (e.g., hormones, genomics) interact to increase an individual's risk of developing PTSD, it is unclear how the underlying neurobiology is shaped by these factors to result in the observed dysregulations. PTSD is marked by impaired cortical control of the limbic system, specifically the amygdala and hippocampus. Fear conditioning approaches have provided robust brain-based phenotypes of PTSD risk regardless of trauma type, as it is observed in both civilian and combat PTSD populations. The proposed study will capitalize on this observable marker and individual variability among women with MST to investigate the neurobiological underpinnings of PTSD as well as the utility of this phenotype to predict treatment response. Using state-of-the art molecular-genetic approaches with a mechanistic understanding of fear circuitry will offer tremendous insight into individual differences in risk and resilience to traum. Fear responses will be observed using a validated fear-potentiated startle paradigm that allows investigators to assess the acquisition, extinction, and return of conditioned fear responses. Hormonal contributions to heightened fear responding will be investigated by measuring estrogen variation in the female Veteran population to be included in this study. The ADCYAP1R1 gene, which codes for the type 1 receptor (PAC1) for pituitary adenylate cyclase activating polypeptide (PACAP) is one of the leading candidate genes related to PTSD in traumatized women. This genetic polymorphism was identified using a hypothesis neutral genomic convergence approach, but has since been replicated in several different PTSD study populations. The proposed project will include the examination of PAC1 genotype, methylation status, mRNA expression, and estrogen variation on PTSD symptom expression as well as laboratory measures of fear and anxiety in an understudied population of female Veterans. Lastly, we will evaluate the predictive nature of the neurobiological indices to be included in the proposed work as they relate to PTSD treatment outcome within the Trauma Recovery Program at the Atlanta VAMC.